TheATP-sensitiveK+ channelisanoctamericproteincomplexthatcontainsfourATP-bindingsubunitscalledSUR subunits. Thesesubunitsareboundbysulfonylurea drugs, whichalsoclosetheK+ channelandarewidelyusedasoralhypoglycemicstotreathyperglycemiainpatientswithpartiallyimpairedbetacellfunction.Hypoglycemiaisasignificantsideeffectofsulfonylureadrugsifusedinexcessorincorrectlyincombinationwithotherdrugs,owingtoinappropriatelyhighreleaseofinsulin.
BothDPP-4–resistant analogues of GLP-1 andinhibitors of DPP-4 arecurrentlyapprovedfortreatmentofpatientswithtype2DMwithsomebetacellfunction.Importantlythesedrugsarepermissive totheactionsofglucoseonthebetacellandthusonlyweaklyincreaseinsulinsecretionintheabsenceofglucose.ThusGLP-1analoguesinducehypoglycemiamuchlessfrequentlythansulfonylureadrugs.
The insulin receptor (InsR) is a member of the receptor tyrosine kinase (RTK) gene family (see ). Most of the actions of insulin on metabolism involve activation of the protein kinase Akt, which in turn has pleiotropic actions on cell metabolism.
The InsR is expressed on the cell membrane as a homodimer, with each monomer containing a tyrosine kinase
B InsRec IRS protein Metabolic actions Anabolic actions of insulin • Utilization of glucose for ATP & anabolic pathways • Storage of FFAs as TG • Protein synthesis from AAs • Macromolecular synthesis (e.g., RNA, DNA, lipids) • Organelle formation • Cell proliferation/renewal Mitogenic actions Merabolic actions PIP2PIP3 RAS/ RAF MAPK/ ERK PI3K Akt
GLUT 4 Translocation Glucose import Glycolysis, Glycogenesis, PDH, DNL Glucogenolysis Gluconeogensis FFA ˜ oxidation Ketogenesis Lipolysis Proteolysis autophagy Protein synthesis Gycolysis, PPP, DNL Gluconeo-genesis, VLDL export Protein phoshatases mTORC1 SREBP-1C FOX01 Akt •Fig. 39.9 A,Structureofdimerizedinsulinreceptorincellmembrane.B,SimplifieddiagramoftheAktkinaseandMAPKpathwaysdownstreamoftheInsR.C,Summarizedactionsofinsulin/InsR-activatedAktkinase.
Insulingeneexpressionandisletcellbiogenesisaredependentonseveraltranscriptionfactorsspecifictothepancreas,liver,andkidney.Thesetranscriptionfactorsincludehepatocyte nuclear factor 4α (HNF-4α), HNF-1α, insulin promoter factor 1 (IPF-1), HNF-1β, and neurogenic differentiation 1/beta cell E-box trans-activator 2 (NeuroD1/β2). Aheterozygousnullmutationofoneofthesefactorsresultsinprogressivelyinadequateproductionofinsulinandmaturity-onset diabetes of the young (MODY) beforetheageof 25.MODYischaracterizedbynonketotichyperglycemia,oftenasymptomatic,thatbeginsinchildhoodoradolescence.Inadditiontothefivetranscriptionfactors,mutationsinglucokinase alsogiverisetoMODY.
•Fig. 39.10 Divergentproteolyticcleavagepatternsoftheproglucagonmolecule.GLUC,glucagon;GLP,glucagon-likepeptide;GRPP,glucagon-relatedpolypeptide.
domain on the cytosolic side (see